Disease mechanisms in myofibrillar myopathy (MFM): Myofibrillar myopathy caused by dominant mutations in the Z-disc associated LIM Domain Binding protein 3 (LDB3) is a prominent distal myopathy defined by the Z-disc disruption, dissolution of actin filaments and accumulations of degraded myofibrillar proteins in the sarcoplasm of muscle fibers. Mutations in at least 8 other Z-disc associated proteins cause a similar muscle pathology indicating shared disease mechanism for this group of myopathies. The disease mechanisms underlying these pathological changes are not yet known. We generated knock-in mice harboring the most common disease -causing mutation p.A165V in mouse Ldb3 gene. These mice reproduce hallmark features of myofibrillar myopathy. Both heterozygous and homozygous mice develop a similar progressive myopathy indicating a toxic gain-of-function by the mutant protein. Unbiased exploratory Next Generation sequencing (RNASeq, microarray and RPPA) have identified key cell signaling pathways affecting calcium signaling, muscle energetics, and protein turnover as potential underlying cellular and molecular disease mechanisms. Importantly, key proteins in these pathways that are abnormally expressed in mutant muscle tissue have been previously identified as direct interactors of LDB3. Currently, we are validating these pathways to establish the role of mutant LDB3 protein in altering the expression of its interactors and causing the hallmark muscle pathology. We anticipate that these pathway alterations will serve as molecular biomarkers for drug dosing and therapeutic response in patients during future clinical trials. There is a growing interest from patient community to develop therapeutics for MFM. Our goals are to define the molecular and cellular targets in these mice for therapeutic development in MFM. The mouse models will be useful in preclinical treatment trials to test therapeutics. Patient studies: We completed the MRI analysis of the NIH Duchenne muscular dystrophy (DMD) Imaging study (2011-N-0261) and published the results. We began the data analysis of 113 patients participated across 6 sites (24 patients at NIH CC) for all 3 study visits in the myotonic dystrophy (DM) clinical research network study (DMCRN; 2014-N-132). We completed the data analysis of the ankle dorsiflexion strength and myotonia measurements in 24 NIH participants (2014-N-0132) by the ankle intellistretch device (developed at the NIH). We enrolled age-and gender matched healthy participants for comparison (n = 5, target n = 10). We developed novel handgrip relaxometer devices to measure hand grip myotonia and conducted a pilot study to characterize and validate the devices in 20 DM1 patients and 10 healthy participants (2014-N-0132). We submitted a new clinical protocol titled,Assessing Clinical Endpoints and Biomarkers in Myotonic Dystrophy Type 1 and Type 2 (ASCEND-DM) (2018-T-N-4295). MFM patients with LDB3 p.A165V mutation have been enrolled for a longitudinal follow up study. We completed exome analysis of about 50 patients with rare undiagnosed neurodegenerative neuromuscular diseases seen in the Neurogenetics Clinic (2000-N-0043) and identified novel mutations, atypical phenotypes and very rare but potentially treatable hereditary neurodegenerative diseases.